Pancreatic cancer is a lethal malignancy with a 5-year survival rate of only 6%. Surgical resection remains the only cure, yet even after resection the 5-year survival is only 20% due to a high recurrence rate. Thus, a high proportion of patients with this disease will ultimately require systemic chemotherapy for advanced pancreatic cancer (APC). While the advent of personalized medicine has resulted in significant advances in the management of many cancer types, the standard of care for pancreatic cancer remains gemcitabine based, with very few exceptions. This article first aims to provide an overview of the benefits and limitations of gemcitabine alone, gemcitabine combinations, and different modes of administration of gemcitabine in APC. It then discusses research, suggesting that pharmacogenomic differences in enzymes that affect gemcitabine transport and metabolism can predict benefit from this drug in pancreatic cancer. Finally, the article outlines novel therapies and combinations that exploit these interindividual variations in gemcitabine metabolism to improve the efficacy of this drug in the management of APC.